In this application, Barrett's esophagus: Predictors of progression, we propose an innovative approach involving three projects that (1) challenges the scientific paradigm that all cancers develop as a result of gradual accumulation of mutations during somatic genomic evolution and (2) seeks to shift the clinical practice paradigm of interventions based a pathologic description at a single point in time to an approach based on disease dynamics that assesses the trajectory of a condition as the somatic genome evolves over time. Each member of the Executive Committee brings complementary expertise to the POl, including genetics, genomics, epidemiology, population genetics, evolutionary biology, biostatistics, bioinformatics, computational biology and medicine. Core A, Administration and Leadership, is essential for inter-project and core communication and collaboration to achieve the overarching goals ofthe POl. The Leadership Core is responsible for planning, implementing, evaluating and coordinating scientific progress at daily, weekly, monthly, and yeariy intervals to assure that that the POl achieves its strategic goals. We have established a network of leadership that extends from the External Advisory Board into each project and core. The Executive Committee meetings are open to everyone in the POl. Study designs, implementation, progress and analysis are all presented and reviewed in regularly scheduled POl meetings (average 2.13 per month in the current funding period). Project and Core Coordinators, under the direction of the Project Leaders and Core Directors, will assure timely implementation of the decisions of the Executive Committee as well as being a vehicle for eariy identification of opportunities and challenges that can be brought to the attention of the Executive Committee. Core A will lead the team of researchers who will provide new tools to identify the group of people with a condition called Barrett's esophagus who are at risk for developing esophageal adenocarcinoma from the group of people with the same condition who will never develop this cancer. The incidence of esophageal adenocarcinoma is rising faster than any other cancer. These new tools will also be helpful in other cancers.